Abstract

Immunosuppressive medications are frequently utilized to manage autoimmune skin disorders, stemming from an overactive immune system. Nonetheless, their prolonged usage in elders can lead to serious side effects. Consequently, continuous monitoring is essential throughout treatment to promptly identify adverse effects. One of the most significant risks is an increased susceptibility to infections. Since immunosuppressants lower the body's natural defenses, patients become more vulnerable to bacterial, viral, and fungal infections. This risk is compounded in older adults, whose immune systems are already less robust. Another major concern is the heightened risk of cancers. The suppression of the immune system can reduce the body's ability to detect and destroy cancerous cells, leading to a higher incidence of malignancies. Additionally, long-term immunosuppressive therapy can cause metabolic issues, including diabetes, hypertension, and osteoporosis, further complicating the health status of elderly patients. Regular check-ups and tests are necessary to identify and manage any adverse effects promptly. This proactive approach helps to mitigate risks, ensuring that the benefits of immunosuppressive treatment outweigh the drawbacks, particularly in vulnerable elderly populations.

Keywords

Introduction

Figure 1 Symmetrical distribution of psoriatic lesions on the back and elbow

Figure 2 Diagrammatic representation of normal to Psoriasis skin

Psoriasis is clinically divided into two categories:

 Pustular and Non-pustular lesions.

• Non-pustular psoriasis:

1. Psoriasis vulgaris (early and late onset)
2. Guttate psoriasis
3. Erythrodermic psoriasis
4. Palmoplantar psoriasis Psoriatic arthritis (PsA)
5. Inverse psoriasis

• Pustular psoriasis:

1. Generalized pustular psoriasis (von Zumbusch type)
2. Impetigo herpetiformis
3. Localized pustular psoriasis

• Palmoplantar pustular psoriasis (Barber type)
• Acrodermatitis continua of Hallopeau

IMMUNOSUPPRESSANT DRUGS

suppress or reduce the strength of the immune system. Some types help prevent organ transplant rejection, while others treat autoimmune disorders like lupus or psoriasis. Immunosuppression encompasses actions that diminish the immune system's efficacy, which may result from interactions within the immune system itself or as an unintended consequence of treating other ailments. The use of immunosuppressive drugs has been demonstrated to cause hyperglycemia and diabetes, both of which are associated with poorer transplant outcomes, increased instances of acute rejections, and infections. Consequently, older transplant recipients are more prone to experiencing negative drug effects from their immunosuppressive treatment, as indicated by higher incidences of diabetes and new malignancies. Additionally, older recipients are dying more often from bacterial infections compared to younger transplant recipients and those still on the waitlist. [4] Immunosuppressive agents are employed to manage severe manifestations of allergies, autoimmune disorders, and transplant-related complications. These agents vary in their impact on the immune system, with some exerting broad effects while others target specific pathways. While drugs with broad effects may induce adverse reactions, those with specific targets could lose efficacy if alternative metabolic routes are activated. Consequently, treatment strategies often employ combinations of drugs to mitigate adverse effects and forestall treatment resistance. Bacteria and viruses primarily cause significant infections in transplant recipients. Notably, older transplant recipients experience higher rates of bacterial infections. [5]Consequently, treatment strategies often employ combinations of drugs to mitigate adverse effects and forestall treatment resistance. Despite the importance of standardized protocols for scientific evaluation, clinicians must remain flexible, adjusting treatment based on ongoing assessments of drug responses, disease progression, and individual patient characteristics.

ELDERLY PATIENTS, typically those over 65 years old, encounter specific challenges related to medications. They often have multiple health conditions and are at a higher risk for adverse reactions to medications.[6] As the population ages, the use of immunosuppressants for preventing organ rejection after transplants or treating autoimmune disorders like rheumatoid arthritis, systemic lupus erythematosus, and inflammatory bowel disease is expected to rise. Over the past 20-25 years, the average age of patients receiving solid organ transplants (SOTs) has increased, with most recipients now being over 50 years old.[7] Age alone is not an absolute contraindication for transplants if the elderly patient has few comorbidities. However, frailty is linked to poorer outcomes both before and after transplantation. Managing elderly patients on immunosuppressants relies heavily on close collaboration with tertiary care providers. Regular check-ups at these institutions for both short- and long-term complications enable timely treatment adjustments and early interventions.[8], [9]

IMMUNOSUPPRESSANT REGIMEN:

Selecting immunosuppressive medication regimens for elderly patients is complex due to the lack of specific guidelines. Recommendations for the elderly are challenging to establish because they are often excluded from studies and clinical trials.[10] The advent of biological agents has revolutionized the treatment of many autoimmune diseases, and future developments will require healthcare professionals to continuously update their clinical knowledge to monitor these effective treatments. Immunosuppression regimens and protocols are constantly evolving, and there is currently no universally accepted consensus to guide therapy.[4] Immunosuppressant doses and serum target levels are personalized based on the indication, disease response, side-effect profile, age, and frailty of the patient. Monitoring frequency may decrease over time but will depend on the individual patient's comorbidities and complications. Therapeutic drug monitoring (TDM) is available for narrow therapeutic index (NTI) immunosuppressants like tacrolimus, cyclosporin, Everolimus, sirolimus, and mycophenolate. However, TDM may not fully capture the effects of Immunosenescence or the overall level of immunosuppression.[11] Due to Immunosenescence, many clinicians may instinctively use lower immunosuppressant doses for elderly patients to reduce the risk of infection and side effects. Still, there is no widely accepted consensus on specific TDM for the elderly.

PHARMACOKINETICS OF IMMUNOSUPPRESSANTS:

In the elderly population, age-related physiological changes can significantly alter the pharmacokinetics of immunosuppressants. These alterations are particularly notable with calcineurin inhibitors (CNIs), where initial doses similar to those for younger patients may lead to higher serum concentrations in older patients. A recent study on optimal CNI dosing in elderly kidney transplant recipients (aged ?65 years) found that serum CNI trough levels were 50% higher in the elderly when adjusted for dose and weight. This increased serum concentration is due to reduced metabolism by CYP3A4 isozymes and decreased P-glycoprotein activity, enhancing bioavailability in the elderly.[12] Consequently, elderly patients often require lower CNI doses to achieve the same therapeutic levels. Conversely, elderly patients typically need higher doses of mycophenolic acid (MPA) compared to younger patients. This need arises because MPA is strongly bound to serum albumin, and lower albumin levels in the elderly lead to increased clearance of unbound MPA. A pharmacokinetic study showed that elderly transplant patients (aged 63 ± 1 years) had lower overall MPA exposure and trough concentrations than younger patients (aged 41 ± 5 years).[13], [14] Data from liver and renal transplant recipients indicated that patients with lower serum albumin required significantly higher mycophenolate doses compared to those with normal serum albumin levels. The metabolism and excretion of methotrexate are also affected by age, necessitating close monitoring of elderly patients.[15], [16] High discontinuation rates due to toxicity, such as nausea, vomiting, myelosuppression, and elevated liver enzymes, are common in this group. However, studies on mammalian targets of rapamycin (mTOR) inhibitors have shown no significant differences in excretion between elderly and younger patients.[17] The effects of aging on the pharmacokinetics of prednisolone remain unknown.[18]

COMORBIDITIES IN PATIENTS RECEIVING IMMUNOSUPPRESSANTS:

Immunosuppressants can cause or worsen comorbidities such as hypertension, renal dysfunction, diabetes, and hyperlipidemia. Without immunosuppression, older patients already face an increased risk of cardiovascular-related disease or death. Cardiovascular disease mortality rates vary by transplant type: approximately 40?ter cardiac and renal transplantation, 20?ter liver transplantation, and 5?ter lung transplantation.[19]The most clinically significant change in the elderly is the decline in renal function, which decreases by about 10% per decade with increasing age.[20]Close monitoring of renal function is essential during methotrexate therapy in the elderly, as many adverse effects are related to impaired renal function.[14], [21] Elderly lung transplant recipients experience higher rates of severe renal dysfunction over the long term compared to younger recipients. Strategies to minimize CNI use with mTOR inhibitors may help preserve renal function in the elderly transplant population.[22], [23], [24] The risk of developing new-onset diabetes mellitus after transplantation (NODAT) increases 1.5-fold with each decade of age following kidney transplant.[25] The incidence of NODAT varies across solid organ transplants: 4-25% in renal transplant recipients, 2-38% in liver transplant recipients, 7-26% in heart transplant recipients, and 32-57% in lung transplant recipients. Immunosuppressants such as corticosteroids, CNIs, and mTOR inhibitors have diabetogenic potential, with corticosteroids having the strongest dose-dependent diabetogenic effect.[26]

INFECTIOUS DISEASE CAUSED BY TAKING IMMUNOSUPPRESSANTS:

Infections are a major cause of morbidity and mortality in elderly patients on immunosuppressants. Immunocompetence decreases with age, making older patients more susceptible to and likely to die from bacterial infections compared to younger transplant recipients. The risk and severity of infection increase with the level of immunosuppression, particularly within the first six months after an organ transplant.[27] Solid organ transplant (SOT) recipients over 50 years old have double the risk of developing bacteremia with septic shock.[28] The incidence of opportunistic infections, such as Pneumocystis jirovecii pneumonia (PJP), herpes zoster, and tuberculosis, has risen with the increased use of biologics.[29] A prospective analysis of patients with inflammatory bowel disease found higher rates of opportunistic infections in those aged 50 years and older, especially when using steroids, thiopurines, and combination immunosuppressant therapy.[30] Immunosuppressive regimens can predispose patients to specific infections; for example, corticosteroids increase the risk of PJP, hepatitis B, and bacterial and fungal infections, while T-lymphocyte depletion can activate latent Cytomegalovirus (CMV) reactivation. Azathioprine has been linked to papillomavirus infections, and mycophenolate to late-onset CMV.[31] General practitioners (GPs) are often involved in the initial management of infections in elderly patients on immunosuppressants. Decisions to withhold or alter doses of immunosuppressive therapy should only be made in close consultation with the transplant physician. Although most infectious complications related to immunosuppression are preventable, they can rapidly become life-threatening, requiring urgent referral for hospital management. Treating infections can destabilize immunosuppressant regimens due to medication interactions and toxicities, such as nephrotoxicity, leukopenias, and hepatotoxicity.  Immunosenescence, the gradual decline of the immune system with age, may increase the risk of malignancy in the elderly due to decreased immunosurveillance.[4] Cancer incidence and mortality rise after the age of 65, peaking around 85–90 years. Transplant recipients face a cancer risk that is approximately two to three times higher than that of the non-transplant population, with this risk correlating to the intensity and duration of immunosuppression.[32] Advanced age is a significant predictor of malignancy in kidney transplant recipients.[33] One study found a five-fold increase in cancer risk for kidney transplant recipients over 60 years old compared to those under 45yrs.[34] Among lung transplant recipients, 40% had at least one malignancy 10 years post-transplantation, with skin cancers being the most common, followed by lymphoproliferative disorders. Recipients over 65 years old had higher rates of skin cancers than younger recipients.[22] mTOR inhibitors may play a role in reducing the risk of malignancy in transplant recipients due to their potential anti-tumor effects.[35]

CONCLUSION:

Age significantly impacts both the immune response and the pharmacokinetics of immunosuppressants. Elderly patients are generally more prone to over-immunosuppression, leading to increased risks of infections and malignancies. The lack of clinical trials including older patients highlights the need for more research focused on this population. Effective management of elderly patients on immunosuppressants requires close surveillance and collaboration among all healthcare providers involved in their care. Collaboration between patients and healthcare providers is essential to ensure treatment decisions are tailored to each individual's unique needs and circumstances.

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